Directly compressible pharmaceutical composition for the oral administration of CCI-779

Inactive Publication Date: 2005-07-14
WYETH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] The present invention provides a convenient and effective method to deliver therapeutic levels of CCI-779 to the patient. The invention provides pharmaceutical compositions containing a stable and bioavailable form of micronized CCI-779, and optionally, an antioxidant or a chelating agent, or mixtures thereof, in an immediate release dosage form for oral administration. The composition is in the form of a tablet or in filled capsules.

Problems solved by technology

One obstacle towards the formulation of CCI-779 is its poor aqueous dissolution and low oral bioavailability.
Additionally, CCI-779 exhibits aqueous instability and has shown its potential to undergo oxidation.
Further, although the resulting tablets were stable and bioavailable, the preparation of the hydroalcoholic solution was very tedious.
Further, CCI-779 was thermodynamically unstable, precipitating within one day after its preparation, requiring it to be used immediately after its preparation.

Method used

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  • Directly compressible pharmaceutical composition for the oral administration of CCI-779

Examples

Experimental program
Comparison scheme
Effect test

example 1

Directly Compressible Tablet Formulations Prepared by Employing Non-Micronized CCI-779

[0035] The compositions included in this example employed non-micronized CCI-779 and were prepared with or without a surfactant. The tabletting was carried out by dry blending and direct compression method.

TABLE 1Quantitative Composition of CCI-779 Tablets, 5 mgContaining Non-Micronized CCI-779 without SurfactantPercentIngredientsWt / WtMg / tabletFunctionCCI-779, non-micronized1.445.00ActiveButylated Hydroxyanisol, NF0.10.35AntioxidantButylated Hydroxytoluene, NF0.050.18AntioxidantEDTA, USP0.010.04Chelating agentSodium Citrate Anhydrous0.752.62pH modifierCitric acid, Anhydrous USP0.250.87pH modifierPovidone, K17, USP7.1424.99Filler / BinderLactose Anhydrous, NF34.30120.05FillerMicrocrystalline Cellulose, NF51.46180.11Filler / Binder(Avicel PH 112)Croscarmellose Sodium, NF4.0014.0DisintegrantMagnesium Stearate, NF0.501.75LubricantTotal0.05350

[0036]

TABLE 2Quantitative Composition of CCI-779 Tablets, 25 m...

example 2

Directly Compressible Tablet Formulations Prepared by Employing Micronized CCI-779, Sodium Lauryl Sulphate and Povidone

[0038] The tablet formulations for this example are manufactured using the following protocol.

[0039] Microcrystalline cellulose (Avicel PH-112) and povidone K-25 are passed through a screen and transferred to a V-blender of suitable size. Micronized CCI-779 is preblended with a portion of lactose anhydrous separately, then passed through a screen and added to the V-blender. Sodium lauryl sulfate, croscarmellose sodium, silicone dioxide and a portion of lactose anhydrous are passed through a screen and transferred to the V blender. The remaining lactose anhydrous is passed through a screen and transferred it to V-blender and the lids are closed. The material is blended without activation of intensifier bar. Magnesium stearate is passed through a screen, premixed with a weight equivalent portion of powder, blended from V-blender, transferred to the lubricant premix ...

example 3

Directly Compressible Tablet Formulations Prepared by Employing Micronized CCI-779 and Poloxamer as Surfactant

[0041] The table formulations for this example are manufactured according to the following protocol.

[0042] Pass the poloxamer 188, microcrystalline cellulose (Avicel PH-112) and a portion of anhydrous lactose through a screen and blend. Mill the blend containing poloxamer with the help of a Fitz mill and transfer it to a V-blender of suitable size.

[0043] Preblend a portion of anhydrous lactose with micronized butylated hydroxyanisole, butylated hydroxytoluene, EDTA calcium disodium, hydrous, and citric acid anhydrous. Then add CCI-779 to this preblend, mix and add to the V-blender.

[0044] Take a portion of anhydrous lactose, croscarmellose sodium, and colloidal silicon dioxide (Aerosil 200) and pass through a screen, blend and transfer it to V-blender. Pass the remaining anhydrous lactose through a screen and transfer it to V-blender. Close the lids and blend the material...

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Abstract

Micronized CCI-779 is described. This directly compressible rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid provides a convenient and effective method to deliver therapeutic levels of CCI-779 to a patient.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application No. 60 / 534,951, filed Jan. 8, 2004.BACKGROUND OF THE INVENTION [0002] Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) is an anticancer agent and is characterized by the following structure. [0003] CCI-779 exhibits cytostatic, as opposed to cytotoxic properties, and may delay the progression of tumors or tumor recurrence. The mechanism of action of CCI-779 that results in the G1 to S phase block is novel for an anticancer drug. In vitro, CCI-779 has been shown to inhibit the growth of a number of histologically diverse tumor cells. Central nervous system (CNS) cancer, leukemia (T-cell), breast cancer, prostate cancer, and melanoma lines were among the most sensitive to CCI-779. The compound arrested cells in the G1 phase of the cell cycle. [0004] CCI-779 has poor water solubility (less than 1 μg / ml) and high permeability (Log ...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61K9/20A61K31/4745
CPCA61K9/14A61K9/2018A61K9/2054A61K31/4745A61P35/00A61P35/04A61K31/4738A61K9/20
InventorASHRAF, MUHAMMADBENJAMIN, ERIC
OwnerWYETH